OBJECTIVE: CD1d-reactive invariant natural killer T (iNKT) cells secrete multiple cytokines upon T cell receptor (TCR) engagement and modulate many immune-mediated conditions. The purpose of this study was to examine the role of these cells in the development of autoimmune disease in genetically lupus-prone (NZBxNZW)F1 (BWF1) mice. METHODS: The CD1d1-null genotype was crossed onto the NZB and NZW backgrounds to establish CD1d1-knockout (CD1d0) BWF1 mice. CD1d0 mice and their wild-type littermates were monitored for the development of nephritis and assessed for cytokine responses to CD1d-restricted glycolipid alpha-galactosylceramide (alphaGalCer), anti-CD3 antibody, and concanavalin A (Con A). Thymus and spleen cells were stained with CD1d tetramers that had been loaded with alphaGalCer or its analog PBS-57 to detect iNKT cells, and the cells were compared between BWF1 mice and class II major histocompatibility complex-matched nonautoimmune strains, including BALB/c, (BALB/cxNZW)F1 (CWF1), and NZW. RESULTS: CD1d0 BWF1 mice had more severe nephritis than did their wild-type littermates. Although iNKT cells and iNKT cell responses were absent in CD1d0 BWF1 mice, the CD1d0 mice continued to have significant numbers of interferon-gamma-producing NKT-like (CD1d-independent TCRbeta+,NK1.1+ and/or DX5+) cells. CD1d deficiency also influenced cytokine responses by conventional T cells: upon in vitro stimulation of splenocytes with Con A or anti-CD3, type 2 cytokine levels were reduced, whereas type 1 cytokine levels were increased or unchanged in CD1d0 mice as compared with their wild-type littermates. Additionally, numbers of thymic iNKT cells were lower in young wild-type BWF1 mice than in nonautoimmune strains. CONCLUSION: Germline deletion of CD1d exacerbates lupus in BWF1 mice. This finding, together with reduced thymic iNKT cells in young BWF1 mice as compared with nonautoimmune strains, implies a regulatory role of CD1d and iNKT cells during the development of lupus.
OBJECTIVE:CD1d-reactive invariant natural killer T (iNKT) cells secrete multiple cytokines upon T cell receptor (TCR) engagement and modulate many immune-mediated conditions. The purpose of this study was to examine the role of these cells in the development of autoimmune disease in genetically lupus-prone (NZBxNZW)F1 (BWF1) mice. METHODS: The CD1d1-null genotype was crossed onto the NZB and NZW backgrounds to establish CD1d1-knockout (CD1d0) BWF1mice. CD1d0 mice and their wild-type littermates were monitored for the development of nephritis and assessed for cytokine responses to CD1d-restricted glycolipid alpha-galactosylceramide (alphaGalCer), anti-CD3 antibody, and concanavalin A (Con A). Thymus and spleen cells were stained with CD1d tetramers that had been loaded with alphaGalCer or its analog PBS-57 to detect iNKT cells, and the cells were compared between BWF1mice and class II major histocompatibility complex-matched nonautoimmune strains, including BALB/c, (BALB/cxNZW)F1 (CWF1), and NZW. RESULTS: CD1d0 BWF1mice had more severe nephritis than did their wild-type littermates. Although iNKT cells and iNKT cell responses were absent in CD1d0 BWF1mice, the CD1d0 mice continued to have significant numbers of interferon-gamma-producing NKT-like (CD1d-independent TCRbeta+,NK1.1+ and/or DX5+) cells. CD1d deficiency also influenced cytokine responses by conventional T cells: upon in vitro stimulation of splenocytes with Con A or anti-CD3, type 2 cytokine levels were reduced, whereas type 1 cytokine levels were increased or unchanged in CD1d0 mice as compared with their wild-type littermates. Additionally, numbers of thymic iNKT cells were lower in young wild-type BWF1mice than in nonautoimmune strains. CONCLUSION: Germline deletion of CD1d exacerbates lupus in BWF1mice. This finding, together with reduced thymic iNKT cells in young BWF1mice as compared with nonautoimmune strains, implies a regulatory role of CD1d and iNKT cells during the development of lupus.
Authors: Caroline G McPhee; Thomas J Sproule; Dong-Mi Shin; Jason A Bubier; William H Schott; Martin P Steinbuck; Lia Avenesyan; Herbert C Morse; Derry C Roopenian Journal: J Immunol Date: 2011-09-30 Impact factor: 5.422
Authors: Christian Kurts; Felix Heymann; Veronika Lukacs-Kornek; Peter Boor; Jürgen Floege Journal: Semin Immunopathol Date: 2007-10-23 Impact factor: 9.623
Authors: Sufi R Morshed; Tsuyoshi Takahashi; Paul B Savage; Neeraja Kambham; Samuel Strober Journal: Clin Immunol Date: 2009-06-28 Impact factor: 3.969
Authors: Gediminas Matulis; Joseph P Sanderson; Nikolai M Lissin; Maria B Asparuhova; Gopal R Bommineni; Daniel Schümperli; Richard R Schmidt; Peter M Villiger; Bent K Jakobsen; Stephan D Gadola Journal: PLoS Biol Date: 2010-06-22 Impact factor: 8.029